Pyridinalkyl-aminoalkyl-IH-indole derivatives having an inhibitory action on 5-HT and serotonin reuptake as antidepressants and anxiolytics

ABSTRACT

Novel indole derivatives of the formula (I), in which X, Y, R 1 , R 1′ , m and n have the meanings indicated in Patent Claim 1, have a strong affinity to the 5-HT 1A  and in some cases to the 5-HT 1D  receptors. The compounds inhibit serotonin reuptake, exhibit serotonin-agonistic and -antagonistic properties and are suitable as antidepressants, anxiolytics and for the treatment of neurodegenerative diseases

The invention relates to indole derivatives of the formula I

in which

-   Y denotes H or A′,-   R¹, R^(1′) each, independently of one another, denote H, A, OH, OA,    CN, Hal, COR⁴ or CH₂R⁴,-   R² denotes H, A, Hal, OH, OA, SA, COOH, COOA′, CHO, COA′, SO₂A′,    NH₂, NHA, NA₂, CH₂NA₂, NHCOA, NHCOAr, NHCOOA, NHSO₂A, NHSO₂Ar,    CH₂NHSO₂A, NHCONH₂, NHCONHA, NHCONA₂, NHCONHAr, CONH₂, CONHA, CONA₂,    SO₂NH₂, SO₂NHA, SO₂NA₂, CH₂SO₂NH₂, CH₂SO₂NHA, CH₂SO₂NA₂,    [C(R⁴R^(4′))]_(p)CN, [C(R⁴R^(4′))]_(p)CF₃, [C(R⁴R^(4′))]_(p)COR⁴,    [C(R⁴R^(4′))]_(p)Ar, —O—[C(R⁴R^(4′))]_(p)Ar or [C(R⁴R^(4′))]_(p)Het,-   R³ denotes H, A, [C(R⁴R^(4′))]_(p)Ar or [C(R⁴R^(4′))]_(p)Het,-   R² and R³ together also denote —CH═CH—CH═CH—, —CH═CH—CH₂—C—H₂— or    —CH₂—CH₂—CH═CH—, in which 1 or 2 CH and/or CH₂ units may be replaced    by N and/or 1, 2, 3 or 4 H atoms may be substituted by Hal, A, OH,    OA, NH₂, NO₂, CN, COOH, COOA, CONH₂, NHCOA, NHCONH₂, NHSO₂A, CHO,    COA, SO₂NH₂ or S(O)_(o)A, —O—CH₂—O— or —O—CH₂—CH₂—O—,-   R⁴, R^(4′) each, independently of one another, denote H, A, OH, OA,    NH₂, NHA, NA₂ or NHCOOA′,-   Ar denotes phenyl, naphthyl or biphenyl, each of which is    unsubstituted or mono-, di- or trisubstituted by Hal, A, OH, OA,    NH₂, NO₂, CN, COOH, COOA, CONH₂, NHCOA, NHCONH₂, NHSO₂A, CHO, COA,    SO₂NH₂ or S(O)_(o)A,-   Het denotes a mono- or bicyclic saturated, unsaturated or aromatic    heterocycle having 1 to 4 N, O and/or S atoms, which may be    unsubstituted or mono-, di- or trisubstituted by carbonyl oxygen,    ═S, ═NH, Hal, A, —(CH₂)_(o)—Ar, —(CH₂)_(o)-cycloalkyl,    —(CH₂)_(o)—OH, —(CH₂)_(o)—NH₂, NO₂, CN, —(CH₂)_(o)—COOH,    —(CH₂)_(o)—COOA, —(CH₂)_(o)—CONH₂, —(CH₂)_(o)—NHCOA, NHCONH₂,    —(CH₂)_(o)—NHSO₂A, CHO, COA′, SO₂NH₂ and/or S(O)_(o)A,-   A denotes unbranched or branched alkyl having 1-10 C atoms, in which    one or two CH₂ groups may be replaced by —CH═CH— groups and/or 1-7 H    atoms may also be replaced by F and/or Cl,-   A′ denotes alkyl having 1 to 6 C atoms or benzyl,-   Hal denotes F, Cl, Br or I and-   m denotes 2, 3, 4, 5 or 6-   n denotes 1, 2, 3 or 4,-   o denotes 0, 1 or 2,-   p denotes 0, 1, 2, 3, 4, 5 or 6,    and pharmaceutically usable derivatives, solvates and stereoisomers    thereof, including mixtures thereof in all ratios.

The invention had the object of finding novel compounds having valuableproperties, in particular those which are used for the preparation ofmedicaments.

Heterocyclic aminoalkylpyridine derivatives are described in WO01/98293. The present invention is to be regarded as a selectioninvention hereto.

Other indole derivatives are known from WO 94/24127, WO 90/05721 or fromJP 05043544.

It has been found that the compounds of the formula I according to theinvention and physiologically acceptable acid-addition salts thereof arewell tolerated and have valuable pharmacological properties since theyhave actions on the central nervous system, in particular 5-HTreuptake-inhibiting actions, in that they influence serotoninergictransmission. In particular, they have a strong affinity to the5-HT_(1A) and in some cases to the 5-HT_(1D) receptors.

Since the compounds also inhibit serotonin reuptake, they areparticularly suitable as antidepressants and anxiolytics. The compoundsexhibit serotonin-agonistic and -antagonistic properties. They inhibitthe binding of tritiated serotonin ligands to hippocampal receptors(Cossery et al., European J. Pharmacol. 140 (1987), 143-155) and inhibitsynaptosomal serotonin reuptake (Sherman et al., Life Sci. 23 (1978),1863-1870). Ex-vivo demonstration of serotonin reuptake inhibition iscarried out using synaptosomal uptake inhibition (Wong et al.,Neuropsychopharmacol. 8 (1993), 23-33) and p-chloroamphetamineantagonism (Fuller et al., J. Pharmacol. Exp. Ther. 212 (1980),115-119). The 5-HT_(1D) affinity can be determined, for example, by themethod described by Pauwels and Palmier in Neuropharmacology, 33, 67(1994).

The binding properties of the compounds of the formula I can bedetermined by known 5-HT_(1A) (serotonin) binding tests (5-HT_(1A)(serotonin) binding test: Matzen et al., J. Med. Chem., 43, 1149-1157,(2000) in particular page 1156 with reference to Eur. J. Pharmacol.:140, 143-155 (1987).

The compounds according to the invention can be employed for thetreatment of diseases which are associated with the serotoninneurotransmitter system and in which high-affinity serotonin receptors(5-HT_(1A) receptors) and/or 5-HT_(1D) receptors are involved.

The compounds of the formula I are therefore suitable both in veterinaryand also in human medicine for the treatment of dysfunctions of thecentral nervous system and of inflammation. They can be used for theprophylaxis and combating of the consequences of cerebral infarction(apoplexia cerebri), such as strokes and cerebral ischaemia, and for thetreatment of extrapyramidal motor side effects of neuroleptics and ofParkinson's disease, for acute and symptomatic therapy of Alzheimer'sdisease and for the treatment of amyotrophic lateral sclerosis. They arelikewise suitable as therapeutic agents for the treatment of brain andspinal cord trauma. In particular, however, they are suitable asmedicament active ingredients for anxiolytics, antidepressants,antipsychotics, neuroleptics, antihypertonics and/or for positivelyinfluencing obsessive-compulsive disorder (OCD), anxiety states, panicattacks, psychoses, anorexia, delusional obsessions, migraine,Alzheimer's disease, sleeping disorders, tardive dyskinesia, learningdisorders, age-dependent memory impairment, eating disorders, such asbulimia, drugs misuse and/or sexual dysfunctions.

An important indication for the administration of the compound of thegeneral formula I are psychoses of all types, in particular mentalillnesses from the schizophrenia group. In addition, the compounds canalso be employed for reducing defects in cognitive ability, i.e. forimproving learning ability and memory. The compounds of the generalformula I are also suitable for combating the symptoms of Alzheimer'sdisease. In addition, the substances of the general formula I accordingto the invention are suitable for the prophylaxis and control ofcerebral infarctions (apoplexia cerebri), such as cerebral strokes andcerebral ischaemia. The substances are furthermore suitable for thetreatment of illnesses such as pathological anxiety states,overexcitation, hyperactivity and attention disorders in children andyouths, severe developmental disorders and disorders of social behaviourwith mental retardation, depression, obsessive disorders in the narrower(OCD) and broader sense (OCSD), certain sexual dysfunctions, sleepingdisorders and disorders in nutrient uptake, and psychiatric symptoms aspart of age dementia and dementia of the Alzheimer's type, i.e.illnesses of the central nervous system in the broadest sense.

The compounds of the formula I are likewise suitable for the treatmentof extrapyramidal motor diseases, for the treatment of side effectswhich occur in the treatment of extrapyramidal motor diseases withconventional anti-Parkinson's medicaments, or for the treatment ofextrapyramidal symptoms (EPS) induced by neuroleptics.

Extrapyramidal motor diseases are, for example, idiopathic Parkinson'sdisease, parkinsonian syndrome, dyskinetic choreatic or dystonicsyndromes, tremor, Gilles de la Torette syndrome, ballismus, musclecramps, restless legs syndrome, Wilson's disease, Lewy bodies dementia,Huntington's and Tourette's syndrome.

The compounds according to the invention are also particularly suitablefor the treatment of neurodegenerative diseases, such as, for example,lathyrism, Alzheimer's, Parkinson's and Huntington's.

The compounds of the formula I are particularly suitable for thetreatment of side effects which occur in the treatment of idiopathicParkinson's disease with conventional Parkinson's medicaments. They cantherefore also be used as add-on therapy in the treatment of Parkinson'sdisease. Known Parkinson's medicaments are drugs such as L-dopa(levodopa) and L-dopa combined with benserazide or carbidopa, dopamineagonists, such as bromocriptine, apomorphine, cabergoline, pramipexole,ropinirole, pergolide, dihydro-α-ergocriptine or lisuride, and allmedicaments which effect stimulation of the dopamine receptor,inhibitors of catechol O-methyl transferase (COMT), such as entacaponeor tolcapone, inhibitors of monoamine oxidase (MAO), such as selegiline,and antagonists of N-methyl D-aspartate (NMDA) receptors, such asamantadine or budipine.

The compounds of the general formula I and tolerated salts and solvatesthereof can thus be employed as active ingredients for medicaments, suchas anxiolytics, antidepressants, neuroleptics and/or antihypertensives.

A measure of the uptake of a medicament active ingredient in an organismis its bioavailability.

If the medicament active ingredient is administered intravenously to theorganism in the form of an injection solution, its absolutebioavailability, i.e. the fraction of the drug which reaches thesystemic blood, i.e. the general circulation, in unchanged form is 100%.

In the case of oral administration of a therapeutic active ingredient,the active ingredient is generally in the form of a solid in theformulation and must therefore first be dissolved so that it is able toovercome the entry barriers, for example the gastrointestinal tract, theoral mucous membrane, nasal membranes or the skin, in particular thestratum corneum, or can be absorbed by the body. Pharmacokinetic data,i.e. on the bioavailability, can be obtained analogously to the methodof J. Shaffer et al, J. Pharm. Sciences, 1999, 88, 313-318.

A further measure of the absorbability of a therapeutic activeingredient is the logD value, since this value is a measure of thelipophilicity of a molecule.

If the compounds of the general formula I are optically active, theformula I covers both each isolated optical antipode and also thecorresponding possibly racemic mixtures in any conceivable composition.

The term solvates of the compounds of the formula I is taken to meanadductions of inert solvent molecules onto the compounds of the formulaI which form owing to their mutual attractive force. Solvates are, forexample, mono- or dihydrates or addition compounds with alcohols, suchas, for example, with methanol or ethanol.

The invention relates to the compounds of the formula I and salts andsolvates thereof according to Claim 1 and to a process for thepreparation of compounds of the formula I and salts and solvatesthereof, characterised in that

-   a) a compound of the formula II

in which

-   X, Y and n have the meanings indicated in Claim 1,-   is reacted with a compound of the formula III

in which

-   L denotes Cl, Br or I and R¹, R^(1′) and m have the meanings    indicated in Claim 1, or-   b) a compound of the formula IV    X—(CH₂)_(n)-L  IV    in which-   L denotes Cl, Br or I and X and n have the meanings indicated in    Claim 1,-   is reacted with a compound of the formula V

in which

-   R¹, R^(1′), Y and m have the meanings indicated in Claim 1, and/or-   a basic or acidic compound of the formula I is converted into one of    its salts or solvates by treatment with an acid or base.

The term pharmaceutically usable derivatives is taken to mean, forexample, the salts of the compounds according to the invention andso-called prodrug compounds.

The term prodrug derivatives is taken to mean compounds of the formula Iwhich have been modified with, for example, alkyl or acyl groups, sugarsor oligopeptides and which are rapidly cleaved in the organism to formthe active compounds according to the invention.

These also include biodegradable polymer derivatives of the compoundsaccording to the invention, as described, for example, in Int. J. Pharm.115, 61-67 (1995).

The invention also relates to mixtures of the compounds of the formula Iaccording to the invention, for example mixtures of two diastereomers,for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.

These are particularly preferably mixtures of stereoisomeric compounds.A denotes alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4,5, 6, 7, 8, 9 or 10 C atoms. A preferably denotes methyl, furthermoreethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl,furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl,1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, furthermore preferably, for example,trifluoromethyl.

A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 Catoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethylor 1,1,1-trifluoroethyl.

A also denotes cycloalkyl.

Cycloalkyl preferably denotes cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl.

A′ preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 C atoms,preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl, trifluoromethyl or benzyl.

—COA or —COA′ (acyl) preferably denotes acetyl, propionyl, furthermorealso butyryl, pentanoyl, hexanoyl or, for example, benzoyl.

Hal preferably denotes F, Cl or Br, but also I.

OA preferably denotes, for example, methoxy, ethoxy, propoxy,isopropoxy, butoxy or tert-butoxy.

R¹ preferably denotes, for example, CN or F, very particularlypreferably CN.

R^(1′) preferably denotes H.

m preferably denotes 4.

n preferably denotes 1 or 2.

R² preferably denotes H, Hal, A, SA, CN, CONH₂, COOA′,—O—[C(R⁴R^(4′))]_(p)Ar, [C(R⁴R^(4′))]_(p)Ar or [C(R⁴R^(4′))]_(p)Het,where Het preferably denotes chromen-2-onyl, thienyl, pyridinyl,pyrimidinyl, indolyl, furyl, pyrrolyl, isoxazolyl imidazolyl, thiazolyl,triazolyl, tetrazolyl, quinolyl or isoquinolyl, each of which isunsubstituted or monosubstituted by Hal or COOA′, and Ar preferablydenotes phenyl.

R³ preferably denotes H, A, Hal or CN.

R² and R³ preferably together also denote —CH═CH—CH═CH—.

R⁴ and R^(4′) preferably denote H.

Ar denotes, for example, unsubstituted phenyl, naphthyl or biphenyl,furthermore preferably phenyl, naphthyl or biphenyl, each of which ismono-, di- or trisubstituted by, for example, A, fluorine, chlorine,bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy,hexyloxy, nitro, cyano, formyl, acetyl, propionyl, trifluoromethyl,amino, methylamino, ethylamino, dimethylamino, diethylamino, benzyloxy,sulfonamido, methylsulfonamido, ethylsulfonamido, propylsulfonamido,butylsulfonamido, dimethylsulfonamido, phenylsulfonamido, carboxyl,methoxycarbonyl, ethoxycarbonyl, aminocarbonyl.

Ar very particularly preferably denotes phenyl.

Het, apart from the possible substituents, denotes, for example, 2- or3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2,4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazol-1-, 4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-,4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-,4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-,7- or 8-2H-benzo-1,4-oxazinyl, furthermore preferably1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or-5-yl, 2,1,3-benzoxadiazol-5-yl or chromenyl. The heterocyclic radicalsmay also be partially or fully hydrogenated. Het can thus also denote,for example, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-,-4- or 5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl,tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or-5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-,-2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl,1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-,-4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl,1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl,hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl,1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl,1,2,3,4-tetrahydro-1-, -2-, -3-, 4-, -5-, -6-, -7- or -8-isoquinolyl,2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H-benzo-1,4-oxazinyl, furthermorepreferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)-phenyl or also3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.

Het particularly preferably denotes chromen-2-onyl, thienyl, pyridinyl,pyrimidinyl, indolyl, furyl, pyrrolyl, isoxazolyl imidazolyl, thiazolyl,triazolyl, tetrazolyl, quinolyl or isoquinolyl, each of which isunsubstituted or monosubstituted by Hal or COOA′.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundscan be expressed by the following sub-formulae Ia to Ih, which conformto the formula I and in which the radicals not designated in greaterdetail have the meaning indicated for the formula I, but in which

-   in Ia R¹ denotes CN or F,    -   R^(1′) denotes H;-   in Ib R⁴, R^(4′) denote H;-   in Ic R² denotes H, Hal, A, SA, CN, CONH₂, COOA′,    —O—[C(R⁴R^(4′))]_(p)Ar, [C(R⁴R^(4′))]_(p)Ar or [C(R⁴R^(4′))]Het,    -   R³ denotes H, A, Hal or CN,    -   R² and R³ together also denote —CH═CH—CH═CH—;-   in Id Het denotes chromen-2-onyl, thienyl, pyridinyl, pyrimidinyl,    indolyl, furyl, pyrrolyl, isoxazolyl, imidazolyl, thiazolyl,    triazolyl, tetrazolyl, quinolyl or isoquinolyl, each of which is    unsubstituted or monosubstituted by Hal or COOA′;-   in Ie Ar denotes phenyl which is unsubstituted or mono-, di- or    trisubstituted by Hal;-   in If

-   -   R¹ denotes CN or F,    -   R^(1′) denotes H,    -   R² denotes H, Hal, A, SA, CN, CONH₂, COOA′,        —O—[C(R⁴R^(4′))]_(p)Ar, [C(R⁴R^(4′))]_(p)Ar or        [C(R⁴R^(4′))]_(p)Het,    -   R³ denotes H, A, Hal or CN,    -   R² and R³ together also denote —CH═CH—CH═CH—,    -   Het denotes chromen-2-onyl, thienyl, pyridinyl, pyrimidinyl,        indolyl, furyl, pyrrolyl, isoxazolyl, imidazolyl, thiazolyl,        triazolyl, tetrazolyl, quinolyl or isoquinolyl, each of which is        unsubstituted or monosubstituted by Hal or COOA′,    -   Ar denotes phenyl which is unsubstituted or mono-, di- or        trisubstituted by Hal,    -   p denotes 0 or 1;

-   in Ig

-   -   R¹ denotes CN or F,    -   R^(1′) denotes H,    -   R² denotes H, Hal, A, SA, CN, CONH₂, COOA′,        —O—[C(R⁴R^(4′))]_(p)Ar, [C(R⁴R^(4′))]_(p)Ar or        [C(R⁴R^(4′))]_(p)Het,    -   R³ denotes H, A, Hal or CN,    -   R² and R³ together also denote —CH═CH—CH═CH—,    -   Ar denotes phenyl,    -   p denotes 0 or 1;

-   in Ih

-   -   R¹ denotes CN or F,    -   R^(1′) denotes H,    -   R² denotes H, Hal, A, SA, CN, CONH₂, COOA′,        —O—[C(R⁴R^(4′))]_(p)Ar, [C(R⁴R^(4′))]_(p)Ar,    -   R³ denotes H, A, Hal or CN,    -   R² and R³ together also denote —CH═CH—CH═CH—,    -   R⁴, R^(4′) denote H,    -   Ar denotes phenyl,    -   p denotes 0 or 1;        and pharmaceutically usable derivatives, solvates and        stereoisomers thereof, including mixtures thereof in all ratios.

The compounds of the formula I according to Claim 1 and also thestarting materials for the preparation thereof are, in addition,prepared by methods known per se, as described in the literature (forexample in the standard works, such as Houben-Weyl, Methoden derorganischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag,Stuttgart), to be precise under reaction conditions which are known andsuitable for the said reactions. Use can also be made here of variantswhich are known per se, but are not mentioned here in greater detail.

If desired, the starting materials can also be formed in situ so thatthey are not isolated from the reaction mixture, but instead areimmediately converted further into the compounds of the formula Iaccording to claim 1.

The starting compounds of the formula II and III are generally known. Ifthey are novel, however, they can be prepared by methods known per se.

Compounds of the formula I can be prepared by nucleophilic substitutionof the leaving group L of the compounds of the formula III, where Ldenotes Cl, Br or I, by the amine nitrogen of the compound of theformula II under standard conditions.

The reaction conditions for nucleophilic substitutions, as describedabove, are adequately known to the person skilled in the art, see alsoOrganikum [Practical Organic Chemistry], 17th Edition, Deutscher Verlagfür Wissenschaften, Berlin 1988.

The reaction is generally carried out in an inert solvent, in thepresence of an acid-binding agent, preferably an alkali or alkalineearth metal hydroxide, carbonate or bicarbonate, or another salt of aweak acid of the alkali or alkaline earth metals, preferably ofpotassium, sodium, calcium or caesium. The addition of an organic base,such as ethyldiisopropylamine, triethylamine, dimethylaniline, pyridineor quinoline, or an excess of the component of the formula II or of thealkylation derivative of the formula III may also be favourable. Thereaction time, depending on the conditions used, is between a fewminutes and 14 days, the reaction temperature is between about 0° and150°, normally between 20° and 130°.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or mono, ethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, N-methylpyrrolidone,dimethylacetamide or dimethylformamide (DMF); nitriles, such asacetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbondisulfide; carboxylic acids, such as formic acid or acetic acid; nitrocompounds, such as nitromethane or nitrobenzene; esters, such as ethylacetate, or mixtures of the said solvents.

Compounds of the formula I can furthermore be obtained by reactingcompounds of the formula IV with compounds of the formula V.

The starting compounds of the formula IV and V are generally known. Ifthey are novel, however, they can be prepared by methods known per se.

The reaction conditions are analogous to those of the reaction betweencompounds of the formula II and compounds of the formula III.

Esters can be saponified, for example, using acetic acid or using NaOHor KOH in water, water/THF or water/dioxane, at temperatures between 0and 100°.

Free amino groups can furthermore be acylated in a conventional mannerusing an acid chloride or anhydride or alkylated using an unsubstitutedor substituted alkyl halide or reacted with CH₃—C(═NH)—OEt,advantageously in an inert solvent, such as dichloromethane or THF,and/or in the presence of a base, such as triethylamine or pyridine, attemperatures between −60 and +30°.

A base of the formula I can be converted into the associatedacid-addition salt using an acid, for example by reaction of equivalentamounts of the base and the acid in an inert solvent, such as ethanol,followed by evaporation. Suitable acids for this reaction are, inparticular, those which give physiologically acceptable salts. Thus, itis possible to use inorganic acids, for example sulfuric acid, sulfurousacid, dithionic acid, nitric acid, hydrohalic acids, such ashydrochloric acid or hydrobromic acid, phosphoric acids, such as, forexample, orthophosphoric acid, sulfamic acid, furthermore organic acids,in particular aliphatic, alicyclic, araliphatic, aromatic orheterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids,for example formic acid, acetic acid, propionic acid, hexanoic acid,octanoic acid, decanoic acid, hexadecanoic acid, octadecanoic acid,pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelicacid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid,citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinicacid, methane- or ethanesulfonic acid, benzenesulfonic acid,trimethoxybenzoic acid, adamantanecarboxylic acid, p-toluenesulfonicacid, glycolic acid, embonic acid, chlorophenoxyacetic acid, asparticacid, glutamic acid, proline, glyoxylic acid, palmitic acid,para-chlorophenoxyisobutyric acid, cyclohexanecarboxylic acid, glucose1-phosphate, naphthalenemono- and -disulfonic acids or laurylsulfuricacid. Salts with physiologically unacceptable acids, for examplepicrates, can be used to isolate and/or purify the compounds of theformula I.

On the other hand, compounds of the formula I can be converted into thecorresponding metal salts, in particular alkali metal or alkaline earthmetal salts, or into the corresponding ammonium salts using bases (forexample sodium hydroxide, potassium hydroxide, sodium carbonate orpotassium carbonate).

The invention also relates to the compounds of the formula I accordingto Claim 1 and physiologically acceptable salts or solvates thereof asmedicament active ingredients.

The invention furthermore relates to compounds of the formula I andphysiologically acceptable salts or solvates thereof as 5HT_(1A) and/or5HT_(1D) agonists and as inhibitors of 5-HT reuptake.

The invention also relates to the compounds of the formula I accordingto Claim 1 and physiologically acceptable salts or solvates thereof foruse in combating diseases.

Compounds of the formula I according to the invention may be chiralowing to their molecular structure and may accordingly occur in variousenantiomeric forms. They can therefore exist in racemic or in opticallyactive form.

Since the pharmaceutical activity of the racemates or stereoisomers ofthe compounds according to the invention may differ, it may be desirableto use the enantiomers. In these cases, the end product or even theintermediates can be separated into enantiomeric compounds by chemicalor physical measures known to the person skilled in the art or evenemployed as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixtureby reaction with an optically active resolving agent. Examples ofsuitable resolving agents are optically active acids, such as the R andS forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,mandelic acid, malic acid, lactic acid, suitably N-protected amino acids(for example N-benzoylproline or N-benzenesulfonylproline), or thevarious optically active camphorsulfonic acids. Also advantageous ischromatographic enantiomer resolution with the aid of an opticallyactive resolving agent (for example dinitrobenzoylphenylglycine,cellulose triacetate or other derivatives of carbohydrates or chirallyderivatised methacrylate polymers immobilised on silica gel). Suitableeluents for this purpose are aqueous or alcoholic solvent mixtures, suchas, for example, hexane/isopropanol/acetonitrile, for example in theratio 82:15:3.

The invention furthermore relates to the use of the compounds of theformula I and/or physiologically acceptable salts thereof for thepreparation of a medicament (pharmaceutical composition), in particularby non-chemical methods. They can be converted here into a suitabledosage form together with at least one solid, liquid and/or semi-liquidexcipient or adjuvant and, if desired, in combination with one or morefurther active ingredients.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically usable derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios, and optionally excipients and/or adjuvants.

The invention furthermore relates to the use of a compound of thegeneral formula I and/or pharmaceutically usable derivatives, solvatesand stereoisomers thereof, including mixtures thereof in all ratios, forthe preparation of a medicament which is suitable for the treatment ofhuman or animal illnesses, in particular illnesses of the centralnervous system, such as pathological stress states, depression and/orpsychoses, for reducing side effects in the treatment of high bloodpressure (for example with a-methyldopa), for the treatment ofendoclinological and/or gynaecological illnesses, for example for thetreatment of agromegaly, hypogonadism, secondary amenorrhoea,post-menstrual syndrome and undesired lactation in puberty and for theprophylaxis and therapy of cerebral illnesses (for example migraine), inparticular in geriatrics, in a similar manner as certain ergotalkaloids, and for the control and prophylaxis of cerebral infarction(apoplexia cerebri), such as cerebral strokes and cerebral ischaemia,for the treatment of extrapyramidal motor diseases, for the treatment ofside effects which occur in the treatment of extrapyramidal motordiseases with conventional anti-Parkinson's medicaments, or for thetreatment of extrapyramidal symptoms (EPS) induced by neuroleptics. Inaddition, the pharmaceutical compositions and medicaments which comprisea compound of the general formula I are suitable for improving cognitiveability and for the treatment of the symptoms of Alzheimer's disease. Inparticular, medicaments of this type are suitable for the treatment ofmental illnesses from the schizophrenia group and for combatingpsychotic anxiety states. For the purposes of the invention, the termtreatment includes the prophylaxis and therapy of human or animalillnesses.

The invention furthermore relates to the use of compounds of the formulaI and/or pharmaceutically usable derivatives, solvates and stereoisomersthereof, including mixtures thereof in all ratios, for the preparationof a medicament for combating diseases which are associated with theserotonin neurotransmitter system and in which high-affinity serotoninreceptors (5-HT_(1A) receptors) and/or 5-HT_(1D) receptors are involved.

The invention furthermore relates to the use of compounds of the formulaI and/or pharmaceutically usable derivatives, solvates and stereoisomersthereof, including mixtures thereof in all ratios, for the preparationof a medicament as anxiolytic, antidepressant, neuroleptic and/orantihypertensive.

The substances of the general formula I are normally administeredanalogously to known, commercially available pharmaceutical compositions(for example bromocriptine and dihydroergocornine), preferably in dosesof between 0.2 and 500 mg, in particular between 0.2 and 15 mg, perdosage unit. The daily dosage unit is between 0.001 and 10 mg per kg ofbody weight. Low doses (of between 0.2 and 1 mg per dosage unit, from0.001 to 0.005 mg per kg of body weight) are particularly suitable forpharmaceutical compositions for the treatment of migraine. A dose ofbetween 10 and 50 mg per dosage unit is preferred for other indications.However, the dose to be administered depends on a multiplicity offactors, for example on the efficacy of the corresponding component, theage, the body weight and the general state of health of the patient.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically usable derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios, and at least one further medicament active ingredient.

The invention also relates to a set (kit) consisting of separate packsof

-   (a) an effective amount of a compound of the formula I and/or    pharmaceutically usable derivatives, solvates and stereoisomers    thereof, including mixtures thereof in all ratios, and-   (b) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may comprise, for example, separateampoules, each containing an effective amount of a compound of theformula I and/or pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient in dissolvedor lyophilised form.

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means: water is added if necessary, thepH is adjusted, if necessary, to values between 2 and 10, depending onthe constitution of the end product, the mixture is extracted with ethylacetate or dichloromethane, the phases are separated, the organic phaseis dried over sodium sulfate and evaporated, and the product is purifiedby chromatography on silica gel, by preparative HPLC and/or bycrystallisation. The purified compounds are optionally freeze-dried.

-   Mass spectrometry (MS):    -   EI (electron impact ionisation) M⁺    -   FAB (fast atom bombardment) (M+H)⁺    -   ESI (electrospray ionisation) (M+H)⁺ (unless stated otherwise)

EXAMPLE 1

The synthesis of the indole unit is carried out analogously to thefollowing scheme:

The synthesis of3-{4-[(5-bromopyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrileis carried out analogously to the following scheme:

1.1 1.3 g of ethyl 5-bromonicotinate are initially introduced in 40 mlof tert-butanol, and 427 mg of sodium borohydride are added. The entiremixture is heated under reflux (100° C.) and under N₂ for one hour. 6 mlof methanol are then added. The mixture is stirred overnight. 10 ml ofwater is added to the reaction solution. The mixture is then extractedwith dichloromethane, dried using sodium sulfate and evaporated in arotary evaporator, giving 300 mg of (5-bromopyridin-3-yl)methanol.

1.2 300 mg of the crude product (5-bromopyridin-3-yl)methanol obtainedpreviously are dissolved in 20 of toluene. 0.2 ml of thionyl chlorideare added, and the mixture is stirred at 100° C. for one hour. Themixture is then evaporated in a rotary evaporator. The oily residuecomprises 3-bromo-5-chloromethylpyridine (315 mg).

1.3 300 mg of 3-bromo-5-chloromethylpyridine and 331 mg of3-(4-aminobutyl)-1H-indole-5-carbonitrile are combined in acetonitrile.415 mg of potassium carbonate and a spatula tip of potassium iodide arethen added. The mixture is boiled under reflux overnight. The mixture isevaporated in a rotary evaporator, and water is added. The mixture isextracted twice with ethyl acetate, dried using sodium sulfate, filteredand evaporated in a rotary evaporator.

390 mg of the crude product are purified with the aid of preparativeHPLC:

-   HPLC column: RP 18 (15 mm) Lichrosorb-   Eluent: A 98 of H₂O, 2 of CH₃CN, 0.1% of TFA B 10 of H₂O, 90 of    CH₃CN, 0.1% of TFA-   UV detection: 225 NM; 1 range-   Flow rate: 10 ml-   Fraction 19-23 contains the desired compound    3-{4-[(5-bromopyridin-3-yl-methyl)amino]butyl}-1H-indole-5-carbonitrile,    bis-TFA salt.-   Yield: 143 mg-   HPLC-ESI-MS (M+H)⁺ 383.

EXAMPLE 2 Preparation of3-{4-[(2-chloro-6-methylpyridin-4-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile

2.1 1.94 g of ethyl 2-chloro-6-methylisonicotinate are initiallyintroduced in 36 ml of tert-butanol, 0.93 g of sodium borohydride isadded, and the mixture is heated to reflux under nitrogen (bathtemperature about 120 C). After 1 h, 9 ml of methanol are added slowly,boiled under reflux overnight.

Conventional work-up gives 1.15 g of(2-chloro-6-methylpyridin-4-yl)-methanol.

2.2 1.14 g of (2-chloro-6-methylpyridin-4-yl)methanol are initiallyintroduced in 50 ml of toluene, and 1.05 ml of thionyl chloride areslowly added dropwise with ice cooling. The mixture is boiled underreflux overnight. After cooling, the solvent is removed, giving2-chloro-4-chloromethyl-6-methylpyridine as brown oil (1.1 g).

2.3 213 mg of 2-chloro-4-chloromethyl-6-methylpyridine and 250 mg of3-(4-aminobutyl)-1H-indole-5-carbonitrile are combined in acetonitrile.276 mg of potassium carbonate and about 3 mg of potassium iodide areadded thereto. The mixture is boiled under reflux overnight. The mixtureis cooled, and the solvent is then removed. 20 ml of water and 20 ml ofethyl acetate are then added.

Conventional work-up gives a brown residue (0.4 g).

Purification is carried out by flash chromatography (eluent: CH₂Cl₂/MeOH97:3), giving 150 mg of3-{4-[(2-chloro-6-methylpyridin-4-ylmethyl)amino]-butyl}-1H-indole-5-carbonitrile,HPLC-ESI-MS (M+H)⁺ 353.

EXAMPLE 3 Preparation of3-{4-[(quinolin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile

126 mg of quinoline-3-carboxaldehyde and 200 mg of3-(4-aminobutyl)-1H-indole-5-carbonitrile are combined in a mixture of 5ml of 1,2-dichloroethane and 2.5 ml of THF. 55 mg of glacial acetic acidare added, and the mixture is stirred at room temperature for 3 hours.380 mg of NaB(OAc)₃ are then added, and stirring is continued at RT for2 days.

Saturated NaHCO₃ solution is added to the batch, which is extractedtwice with ethyl acetate, dried over Na₂SO₄, filtered and evaporated ina rotary evaporator. Chromatography in the Flash-Master with EE/MeOH aseluent give 73 mg of the desired product, HPLC-MS (M+H)⁺ 355.

The following compounds are obtained analogously

-   3-{4-[(quinolin-2-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,    HPLC-MS (M+H)⁺ 355;-   3-{4-[(quinolin-4-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,    HPLC-MS (M+H)⁺ 355.

EXAMPLE 4

The following compounds are obtained analogously to Example 1

-   3-{4-[(pyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,    dihydrochloride, HPLC-MS (M+H)⁺ 305;-   3-{4-[(pyridin-2-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,    dihydrochloride, HPLC-MS (M+H)⁺ 305;-   3-{4-[(pyridin-4-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,    dihydrochloride, HPLC-MS (M+H)⁺ 305;-   3-(4-{[5-(4-fluorophenyl)pyridin-3-ylmethyl]amino}butyl)-1H-indole-5-carbonitrile,    HPLC-MS (M+H)⁺ 399;-   3-[4-(2-pyridin-4-ylethylamino]butyl]-1H-indole-5-carbonitrile,    HPLC-MS (M+H)⁺ 319;-   3-{4-[(2,6-dichloropyridin-4-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,    HPLC-MS (M+H)⁺ 373;-   3-{4-[(2-chloropyridin-4-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,    HPLC-MS (M+H)⁺ 339;-   3-{4-[(2-methylpyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,    HPLC-MS (M+H)⁺ 318;-   3-{4-[(6-chloropyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,    bis-TFA salt, HPLC-MS (M+H)⁺ 339;-   3-(4-{[2-(4-chlorophenoxy)pyridin-3-ylmethyl]amino}butyl)-1H-indole-5-carbonitrile,    TFA salt, HPLC-MS (M+H)⁺ 431;-   3-{4-[(2-methylsulfanylpyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,    TFA salt, HPLC-MS (M+H)⁺ 351;-   3-{4-[(2,5-dichloropyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,    bis-TFA salt, HPLC-MS (M+H)⁺ 374;-   3-{4-[(2,6-dichloropyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,    bis-TFA salt, HPLC-MS (M+H)⁺ 374;-   3-{4-[(5-methylpyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,    bis-TFA salt, HPLC-MS (M+H)⁺ 318;-   3-{4-[(6-trifluoromethylpyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,    HPLC-MS (M+H)⁺ 373;-   3-{4-[(4-phenylpyridin-2-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,    HPLC-MS (M+H)⁺ 381;-   3-{4-[(4-phenylpyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,    HPLC-MS (M+H)⁺ 381;-   3-{4-[(5-cyano-6-methylsulfanylpyridin-2-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,    HPLC-MS (M+H)⁺ 376;-   3-{4-[(5-phenylpyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,    HPLC-MS (M+H)⁺ 381;-   3-{4-[(5-phenylpyridin-2-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,    HPLC-MS (M+H)⁺ 381;-   3-[4-(methylpyridin-3-ylmethylamino)butyl]-1H-indole-5-carbonitrile,    HPLC-MS (M+H)⁺ 319.

The examples below relate to pharmaceutical compositions:

EXAMPLE A Injection Vials

A solution of 100 g of an active ingredient of the formula I and 5 g ofdisodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH6.5 using 2N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions. Each injection vial contains 5 mg of activeingredient.

EXAMPLE B Suppositories

A mixture of 20 g of an active ingredient of the formula I is meltedwith 100 g of soya lecithin and 1400 g of cocoa butter, poured intomoulds and allowed to cool. Each suppository contains 20 mg of activeingredient.

EXAMPLE C Solution

A solution is prepared from 1 g of an active ingredient of the formulaI, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g ofVaseline under aseptic conditions.

EXAMPLE E Tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed to give tablets in a conventional manner in such away that each tablet contains 10 mg of active ingredient.

EXAMPLE F Coated Tablets

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE G Capsules

2 kg of active ingredient of the formula I are introduced into hardgelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

EXAMPLE H Ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

EXAMPLE I Inhalation Spray

14 g of active ingredient of the formula I are dissolved in 10 l ofisotonic NaCl solution, and the solution is transferred intocommercially available spray containers with a pump mechanism. Thesolution can be sprayed into the mouth or nose. One spray shot (about0.1 ml) corresponds to a dose of about 0.14 mg.

1. A compound of formula I

in which X is

Y is H or A′, R¹ is CN or F, R¹′ is H, R² is H, Hal, A, SA, CN, CONH₂,COOA′, —O—[C(R⁴R⁴′)]_(p)Ar, [C(R⁴R⁴′)]_(p)Ar or [C(R⁴R⁴′)]_(p)Het, R³ isH, A, Hal or CN, or R² and R³ together are —CH═CH—CH═CH—, R⁴ and R⁴′ areeach H, Ar is phenyl which is unsubstituted or mono-, di- ortrisubstituted by Hal, Het is chromen-2-onyl, thienyl, pyridinyl,pyrimidinyl, indolyl, furyl, pyrrolyl, isoxazolyl, imidazolyl,thiazolyl, triazolyl, tetrazolyl, quinolyl or isoquinolyl, each of whichis unsubstituted or monosubstituted by Hal or COOA′, A is unbranched orbranched alkyl having 1-10 C atoms, in which one or two CH₂ groups areoptionally, each independently, replaced by a —CH═CH— group and/or 1-7 Hatoms are optionally replaced by F and/or Cl, A′ is alkyl having 1 to 6C atoms or benzyl, Hal is F, Cl, Br or I, m is 2, 3, 4, 5 or 6, n is 1,2, 3 or 4, and p is 0, 1, 2, 3, 4, 5 or 6, or a pharmaceuticallyacceptable salt, or stereoisomer thereof, or a mixture thereof.
 2. Acompound according to claim 1, in which p is 0 or
 1. 3. A compoundaccording to claim 1, in which Ar is phenyl, and p is 0 or
 1. 4. Acompound according to claim 1, in which Ar is phenyl, and p is 0 or 1.5. A compound according to claim 1, which is3-{4-[(5-bromopyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(pyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(pyridin-2-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(pyridin-4-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-(4-{[5-(4-fluorophenyl)pyridin-3-ylmethyl]amino}butyl)-1H-indole-5-carbonitrile,3-{4-[(quinolin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-[4-(2-pyridin-4-ylethylamino]butyl]-1H-indole-5-carbonitrile,3-{4-[(2,6-dichloropyridin-4-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(2-chloro-6-methylpyridin-4-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(2-chloropyridin-4-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(2-methylpyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(6-chloropyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-(4-{[2-(4-chlorophenoxy)pyridin-3-ylmethyl]amino}butyl)-1H-indole-5-carbonitrile,3-{4-[(2-methylsulfanylpyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(2,5-dichloropyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(2,6-dichloropyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(5-methylpyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(6-trifluoromethylpyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(quinolin-2-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(4-phenylpyridin-2-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(quinolin-4-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(4-phenylpyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(5-cyano-6-methylsulfanylpyridin-2-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(5-phenylpyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(5-phenylpyridin-2-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,or 3-[4-(methylpyridin-3-ylmethylamino)butyl]-1H-indole-5-carbonitrile.6. A process for preparing a compound of formula I according to claim 1,comprising a) reacting a compound of formula II

in which X is

Y is H or A′, R² is H, Hal, A, SA, CN, CONH₂, COOA′,—O—[C(R⁴R⁴′)]_(p)Ar, [C(R⁴R⁴′)]_(p)Ar or [C(R⁴R⁴′)]_(p)Het, R³ is H, A,Hal or CN, or R² and R³ together are —CH═CH—CH═CH—, R⁴ and R⁴ ′ are eachH, Ar is phenyl which is unsubstituted or mono-, di- or trisubstitutedby Hal, Het is chromen-2-onyl, thienyl, pyridinyl, pyrimidinyl, indolyl,furyl, pyrrolyl, isoxazolyl, imidazolyl, thiazolyl, triazolyl,tetrazolyl, quinolyl or isoquinolyl, each of which is unsubstituted ormonosubstituted by Hal or COOA′, A is unbranched or branched alkylhaving 1-10 C atoms, in which one or two CH₂ groups are optionally, eachindependently, replaced by a —CH═CH— group and/or 1-7 H atoms areoptionally replaced by F and/or Cl, A′ is alkyl having 1 to 6 C atoms orbenzyl, Hal is F, Cl, Br or I, n is 1, 2, 3 or 4, and p is 0, 1, 2, 3,4, 5 or 6, with a compound of formula III

in which L is Cl, Br or I, R¹ is CN or F, R¹′ is H, and m is 2, 3, 4, 5or 6, or b) reacting a compound of formula IV

in which L is Cl, Br or I, X is

R² is H, Hal, A, SA, CN, CONH₂, COOA′, —O—[C(R⁴R⁴′)]_(p)Ar,[C(R⁴R⁴′)]_(p)Ar or [C(R⁴R⁴′)]_(p)Het, R³ is H, A, Hal or CN, or R² andR³ together are —CH═CH—CH═CH—, R⁴ and R⁴′ are each H, Ar is phenyl whichis unsubstituted or mono-, di- or trisubstituted by Hal, Het ischromen-2-onyl, thienyl, pyridinyl, pyrimidinyl, indolyl, furyl,pyrrolyl, isoxazolyl, imidazolyl, thiazolyl, triazolyl, tetrazolyl,quinolyl or isoquinolyl, each of which is unsubstituted ormonosubstituted by Hal or COOA′, A is unbranched or branched alkylhaving 1-10 C atoms, in which one or two CH₂ groups are optionally, eachindependently, replaced by a —OH═CH— group and/or 1-7 H atoms areoptionally replaced by F and/or Cl, A′ is alkyl having 1 to 6 C atoms orbenzyl, Hal is F, Cl, Br or I, n is 1, 2, 3 or 4, and p is 0, 1, 2, 3,4, 5 or 6, with a compound of formula V

in which Y is H or A′, R¹ is CN or F, R¹′ is H, A′ is alkyl having 1 to6 C atoms or benzyl, and m is 2, 3, 4, 5 or 6, and/or converting a basicor acidic compound of formula I into one of its salts and/or solvate bytreatment with an acid or base, or with a solvent.
 7. A pharmaceuticalcomposition comprising a compound according to claim 1 and apharmaceutically acceptable excipient and/or adjuvant.
 8. A method fortreating anxiety, depression, or psychoses, comprising administering toa subject in need thereof an effective amount of a compound of claim 1.9. A kit comprising separate packs of a compound according to claim 1,and a pharmaceutically acceptable excipient and/or adjuvant.
 10. Acompound of formula I

in which X is

Y is H or A′, R¹ is CN or F, R¹′ is H, R² is H, Hal, A, SA, CN, CONH₂,COOA′, —O—[C(R⁴R⁴′)]_(p)Ar, [C(R⁴R⁴′)]_(p)Ar or [C(R⁴R⁴′)]_(p)Het, R³ isH, A, Hal or CN, or R² and R³ together are —CH═CH—CH═CH—, R⁴ and R⁴′ areeach H, Ar is phenyl which is unsubstituted or mono-, di- ortrisubstituted by Hal, Het is chromen-2-onyl, thienyl, pyridinyl,pyrimidinyl, indolyl, furyl, pyrrolyl, isoxazolyl, imidazolyl,thiazolyl, triazolyl, tetrazolyl, quinolyl or isoquinolyl, each of whichis unsubstituted or monosubstituted by Hal or COOA′, A is unbranched orbranched alkyl having 1-10 C atoms, in which one or two CH₂ groups areoptionally, each independently, replaced by a —CH═CH— group and/or 1-7 Hatoms are optionally replaced by F and/or Cl, A′ is alkyl having 1 to 6C atoms or benzyl, Hal is F, Cl, Br or I, m is 2, 3, 4, 5 or 6, n is 1,2, 3 or 4, and p is 0, 1, 2, 3, 4, 5 or 6, or a pharmaceuticallyacceptable salt thereof.
 11. A pharmaceutically acceptable salt of acompound of claim 10, wherein the compound is3-{4-[(5-bromopyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(pyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(pyridin-2-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(pyridin-4-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-(4-{[5-(4-fluorophenyl)pyridin-3-ylmethyl]amino}butyl)-1H-indole-5-carbonitrile,3-{4-[(quinolin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-[4-(2-pyridin-4-ylethylamino]butyl]-1H-indole-5-carbonitrile,3-{4-[(2,6-dichloropyridin-4-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(2-chloro-6-methylpyridin-4-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(2-chloropyridin-4-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(2-methylpyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(6-chloropyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-(4-{[2-(4-chlorophenoxy)pyridin-3-ylmethyl]amino}butyl)-1H-indole-5-carbonitrile,3-{4-[(2-methylsulfanylpyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(2,5-dichloropyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(2,6-dichloropyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(5-methylpyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(6-trifluoromethylpyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(quinolin-2-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(4-phenylpyridin-2-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(quinolin-4-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(4-phenylpyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(5-cyano-6-methylsulfanylpyridin-2-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(5-phenylpyridin-3-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,3-{4-[(5-phenylpyridin-2-ylmethyl)amino]butyl}-1H-indole-5-carbonitrile,or 3-[4-(methylpyridin-3-ylmethylamino)butyl]-1H-indole-5-carbonitrile.